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Ogata T, Sakai T, Shibata S, Kanno H, Nakane H, Aoyagi T, Koikawa K, Sadakari Y, Hirokata G, Taniguchi M. Spontaneous clearance of serum HCV-RNA after splenectomy in a patient with HCV-related liver cirrhosis and portal hypertension: a case report. Surg Case Rep 2024; 10:94. [PMID: 38647617 PMCID: PMC11035502 DOI: 10.1186/s40792-024-01899-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 04/13/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Spontaneous clearance of chronic hepatitis C virus (HCV) is rare in adults. A T-lymphocyte response is thought to be involved in HCV-RNA clearance. Splenectomy reportedly has a beneficial effect on T cell immune function in patients with cirrhosis. To the best of our knowledge, the present report is the first to describe spontaneous clearance of serum HCV-RNA within 1 year after splenectomy in a patient with cirrhosis. CASE PRESENTATION A 55-year-old man with HCV cirrhosis was transferred to our institution with advanced pancytopenia, splenomegaly, and gastric varices. He had a 1-year history of ascites, edema, and general fatigue. The patient had a Child-Pugh score of 8 and serological type 1 HCV; the HCV-RNA level was 4.7 log IU/mL. Contrast-enhanced computed tomography showed gastric varices and marked splenomegaly (estimated spleen volume of 2175 mL). Esophagogastroduodenoscopy revealed enlarged gastric varices with no red color sign, and the varices were larger than those 1 year prior. He was diagnosed with decompensated HCV-related liver cirrhosis and portal hypertension. We considered direct-acting antiviral (DAA) therapy; however, DAA therapy was not approved in Japan for patients with decompensated cirrhosis at that time. Hand-assisted laparoscopic splenectomy was performed to improve the worsening portal hypertension. Further, we planned the initiation of DAA therapy after surgery, when such therapy would become available. DAA therapy was approved 1 year after splenectomy. At that time, we measured the HCV-RNA level before the initiation of DAA therapy; unexpectedly, however, serum HCV-RNA was not detectable, and the virus continued to disappear during the following 4 years. His liver function (total bilirubin, albumin, and prothrombin time) and pancytopenia improved during the 5 years postoperatively. The serum aspartate and alanine aminotransferase levels normalized between 1 and 5 years postoperatively. Esophagogastroduodenoscopy showed no change in the gastric varices during the 5 years after surgery. The patient remained asymptomatic and continued to do well. CONCLUSIONS We have presented a case of spontaneous clearance of HCV-RNA after splenectomy in a patient with cirrhosis and portal hypertension. Splenectomy may be associated with disappearance of HCV-RNA based on previous reports. More cases should be accumulated and evaluated.
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Affiliation(s)
- Toshiro Ogata
- Department of Surgery, St. Mary's Hospital, 422 Tsubukuhonmachi, Kurume, Fukuoka, 830-8543, Japan.
| | - Terufumi Sakai
- Department of Gastroenterology, St. Mary's Hospital, 422 Tsubukuhonmachi, Fukuoka, Kurume, 830-8543, Japan
| | - Sho Shibata
- Department of Gastroenterology, St. Mary's Hospital, 422 Tsubukuhonmachi, Fukuoka, Kurume, 830-8543, Japan
| | - Hiroki Kanno
- Department of Surgery, St. Mary's Hospital, 422 Tsubukuhonmachi, Kurume, Fukuoka, 830-8543, Japan
| | - Hiroyuki Nakane
- Department of Surgery, St. Mary's Hospital, 422 Tsubukuhonmachi, Kurume, Fukuoka, 830-8543, Japan
| | - Takeshi Aoyagi
- Department of Surgery, St. Mary's Hospital, 422 Tsubukuhonmachi, Kurume, Fukuoka, 830-8543, Japan
| | - Kazuhiro Koikawa
- Department of Surgery, St. Mary's Hospital, 422 Tsubukuhonmachi, Kurume, Fukuoka, 830-8543, Japan
| | - Yoshihiko Sadakari
- Department of Surgery, St. Mary's Hospital, 422 Tsubukuhonmachi, Kurume, Fukuoka, 830-8543, Japan
| | - Gentaro Hirokata
- Department of Surgery, St. Mary's Hospital, 422 Tsubukuhonmachi, Kurume, Fukuoka, 830-8543, Japan
| | - Masahiko Taniguchi
- Department of Surgery, St. Mary's Hospital, 422 Tsubukuhonmachi, Kurume, Fukuoka, 830-8543, Japan
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Balasko AL, Kowatsch MM, Graydon C, Lajoie J, Fowke KR. The effect of blocking immune checkpoints LAG-3 and PD-1 on human invariant Natural Killer T cell function. Sci Rep 2023; 13:10082. [PMID: 37344517 DOI: 10.1038/s41598-023-36468-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 06/04/2023] [Indexed: 06/23/2023] Open
Abstract
Invariant Natural Killer T (iNKT) cells undergo immune exhaustion during chronic activation caused by cancer and viral infections, such as HIV. Exhaustion is marked by cell dysfunction and increased expression of immune checkpoint proteins programmed cell-death-1 (PD-1) and lymphocyte-activation-gene-3 (LAG-3). We hypothesize that blockade of PD-1 and/or LAG-3 will enhance iNKT cell function. Utilizing peripheral blood mononuclear cells from healthy donors, LAG-3 and PD-1 expression on iNKT cells was assessed using flow cytometry following in vitro stimulation with iNKT-specific stimulant α-galactosylceramide (n = 4). Efficacy of anti-LAG-3 and/or anti-PD-1 antibody blockades in enhancing iNKT cell function was assessed by determining proliferative capacity and IFN-γ production (n = 9). LAG-3 and PD-1 expression on iNKT cells peaked at Day 4 (98.8%; p ≤ 0.0001 and 98.8%; p = 0.005, respectively), followed by steep decrease by Day 10, coinciding with peak iNKT cell proliferation. In a 10-day blocking assay, both the anti-PD-1 alone and dual anti-PD-1 and anti-LAG-3 significantly increased iNKT proliferation (6 and 6.29 log2 fold-change respectively) compared to the no blockade control (ANOVA-p = 0.0005) with the dual blockade system being more effective (t-test-p = 0.013). This provides proof-of-concept for LAG-3 and PD-1 as immunotherapeutic targets to enhance human iNKT cell function, with the long-term goal of addressing immune exhaustion.
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Affiliation(s)
- Allison L Balasko
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Monika M Kowatsch
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Colin Graydon
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Julie Lajoie
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
- Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
| | - Keith R Fowke
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada.
- Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya.
- Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada.
- Partners for Health and Development in Africa, Nairobi, Kenya.
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Papanastasatou M, Verykokakis M. Innate-like T lymphocytes in chronic liver disease. Front Immunol 2023; 14:1114605. [PMID: 37006304 PMCID: PMC10050337 DOI: 10.3389/fimmu.2023.1114605] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/28/2023] [Indexed: 03/17/2023] Open
Abstract
In addition to its metabolic activities, it is now clear that the liver hosts a number of diverse immune cell types that control tissue homeostasis. Foremost among these are innate-like T lymphocytes, including natural killer T (NKT) and mucosal-associated innate T (MAIT) cells, which are a population of specialized T cells with innate characteristics that express semi-invariant T cell receptors with non-peptide antigen specificity. As primary liver residents, innate-like T cells have been associated with immune tolerance in the liver, but also with a number of hepatic diseases. Here, we focus on the biology of NKT and MAIT cells and how they operate during the course of chronic inflammatory diseases that eventually lead to hepatocellular carcinoma.
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Gu X, Chu Q, Ma X, Wang J, Chen C, Guan J, Ren Y, Wu S, Zhu H. New insights into iNKT cells and their roles in liver diseases. Front Immunol 2022; 13:1035950. [PMID: 36389715 PMCID: PMC9643775 DOI: 10.3389/fimmu.2022.1035950] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 10/14/2022] [Indexed: 08/29/2023] Open
Abstract
Natural killer T cells (NKTs) are an important part of the immune system. Since their discovery in the 1990s, researchers have gained deeper insights into the physiology and functions of these cells in many liver diseases. NKT cells are divided into two subsets, type I and type II. Type I NKT cells are also named iNKT cells as they express a semi-invariant T cell-receptor (TCR) α chain. As part of the innate immune system, hepatic iNKT cells interact with hepatocytes, macrophages (Kupffer cells), T cells, and dendritic cells through direct cell-to-cell contact and cytokine secretion, bridging the innate and adaptive immune systems. A better understanding of hepatic iNKT cells is necessary for finding new methods of treating liver disease including autoimmune liver diseases, alcoholic liver diseases (ALDs), non-alcoholic fatty liver diseases (NAFLDs), and liver tumors. Here we summarize how iNKT cells are activated, how they interact with other cells, and how they function in the presence of liver disease.
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Affiliation(s)
- Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Ma
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanli Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shanshan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Cheng Z, Lin P, Cheng N. HBV/HIV Coinfection: Impact on the Development and Clinical Treatment of Liver Diseases. Front Med (Lausanne) 2021; 8:713981. [PMID: 34676223 PMCID: PMC8524435 DOI: 10.3389/fmed.2021.713981] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/23/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a common contributor to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Approximately 10% of people with human immunodeficiency virus (HIV) also have chronic HBV co-infection, owing to shared transmission routes. HIV/HBV coinfection accelerates the progression of chronic HBV to cirrhosis, end-stage liver disease, or hepatocellular carcinoma compared to chronic HBV mono-infection. HBV/HIV coinfection alters the natural history of hepatitis B and renders the antiviral treatment more complex. In this report, we conducted a critical review on the epidemiology, natural history, and pathogenesis of liver diseases related to HBV/HIV coinfection. We summarized the novel therapeutic options for these coinfected patients.
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Affiliation(s)
- Zhimeng Cheng
- Department of Bile Duct Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Panpan Lin
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Nansheng Cheng
- Department of Bile Duct Surgery, West China Hospital, Sichuan University, Chengdu, China
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Catafal-Tardos E, Baglioni MV, Bekiaris V. Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in γδ T, MAIT, and NKT Cells. Cancers (Basel) 2021; 13:cancers13184647. [PMID: 34572874 PMCID: PMC8467786 DOI: 10.3390/cancers13184647] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/12/2021] [Accepted: 09/13/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary All conventional major histocompatibility complex (MHC)-restricted T cells transiently express immune checkpoint/inhibitory receptors (ICRs) following activation as a means to counter-regulate overactivation. However, tumors promote chronic ICR expression rendering T cells chronically unresponsive or “exhausted”. Checkpoint inhibitor (CPI) therapy targets and blocks ICRs, restoring T cell activation and anti-tumor immunity. However, CPI therapy often fails, partly because of the tumor’s many abilities to inhibit MHC-driven T cell responses. In this regard, our immune system contains an arsenal of unconventional non-MHC-restricted T cells, whose importance in anti-tumor immunity is rapidly gaining momentum. There is currently little knowledge as to whether unconventional T cells can get exhausted and how CPI therapy affects them. In this article we review the current understanding of the role of ICRs in unconventional T cell biology and discuss the importance of targeting these unique immune cell populations for CPI therapy. Abstract In recent years, checkpoint inhibitor (CPI) therapy has shown promising clinical responses across a broad range of cancers. However, many patients remain unresponsive and there is need for improvement. CPI therapy relies on antibody-mediated neutralization of immune inhibitory or checkpoint receptors (ICRs) that constitutively suppress leukocytes. In this regard, the clinical outcome of CPI therapy has primarily been attributed to modulating classical MHC-restricted αβ T cell responses, yet, it will inevitably target most lymphoid (and many myeloid) populations. As such, unconventional non-MHC-restricted gamma delta (γδ) T, mucosal associated invariant T (MAIT) and natural killer T (NKT) cells express ICRs at steady-state and after activation and may thus be affected by CPI therapies. To which extent, however, remains unclear. These unconventional T cells are polyfunctional innate-like lymphocytes that play a key role in tumor immune surveillance and have a plethora of protective and pathogenic immune responses. The robust anti-tumor potential of γδ T, MAIT, and NKT cells has been established in a variety of preclinical cancer models and in clinical reports. In contrast, recent studies have documented a pro-tumor effect of innate-like T cell subsets that secrete pro-inflammatory cytokines. Consequently, understanding the mechanisms that regulate such T cells and their response to CPI is critical in designing effective cancer immunotherapies that favor anti-tumor immunity. In this Review, we will discuss the current understanding regarding the role of immune checkpoint regulation in γδ T, MAIT, and NKT cells and its importance in anti-cancer immunity.
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Khan MA, Khan A. Role of NKT Cells during Viral Infection and the Development of NKT Cell-Based Nanovaccines. Vaccines (Basel) 2021; 9:vaccines9090949. [PMID: 34579186 PMCID: PMC8473043 DOI: 10.3390/vaccines9090949] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 08/16/2021] [Accepted: 08/23/2021] [Indexed: 12/30/2022] Open
Abstract
Natural killer T (NKT) cells, a small population of T cells, are capable of influencing a wide range of the immune cells, including T cells, B cells, dendritic cells and macrophages. In the present review, the antiviral role of the NKT cells and the strategies of viruses to evade the functioning of NKT cell have been illustrated. The nanoparticle-based formulations have superior immunoadjuvant potential by facilitating the efficient antigen processing and presentation that favorably elicits the antigen-specific immune response. Finally, the immunoadjuvant potential of the NKT cell ligand was explored in the development of antiviral vaccines. The use of an NKT cell-activating nanoparticle-based vaccine delivery system was supported in order to avoid the NKT cell anergy. The results from the animal and preclinical studies demonstrated that nanoparticle-incorporated NKT cell ligands may have potential implications as an immunoadjuvant in the formulation of an effective antiviral vaccine that is capable of eliciting the antigen-specific activation of the cell-mediated and humoral immune responses.
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Li C, Chi H, Deng S, Wang H, Yao H, Wang Y, Chen D, Guo X, Fang JY, He F, Xu J. THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy. J Immunother Cancer 2021; 9:e002443. [PMID: 34341130 PMCID: PMC8330570 DOI: 10.1136/jitc-2021-002443] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The abnormal upregulation of programmed death-ligand 1 (PD-L1) in cancer cells inhibits T cell-mediated cytotoxicity, but the molecular mechanisms that drive and maintain PD-L1 expression are still incompletely understood. METHODS Combined analyses of genomes and proteomics were applied to find potential regulators of PD-L1. In vitro experiments were performed to investigate the regulatory mechanism of PD-L1 by thyroid adenoma associated gene (THADA) using human colorectal cancer (CRC) cells. The prevalence of THADA was analyzed using CRC tissue microarrays by immunohistochemistry. T cell killing assay, programmed cell death 1 binding assay and MC38 transplanted tumor models in C57BL/6 mice were developed to investigate the antitumor effect of THADA. RESULTS THADA is critically required for the Golgi residency of PD-L1, and this non-redundant, coat protein complex II (COPII)-associated mechanism maintains PD-L1 expression in tumor cells. THADA mediated the interaction between PD-L1 as a cargo protein with SEC24A, a module on the COPII trafficking vesicle. Silencing THADA caused absence and endoplasmic reticulum (ER) retention of PD-L1 but not major histocompatibility complex-I, inducing PD-L1 clearance through ER-associated degradation. Targeting THADA substantially enhanced T cell-mediated cytotoxicity, and increased CD8+ T cells infiltration in mouse tumor tissues. Analysis on clinical tissue samples supported a potential role of THADA in upregulating PD-L1 expression in cancer. CONCLUSIONS Our data reveal a crucial cellular process for PD-L1 maturation and maintenance in tumor cells, and highlight THADA as a promising target for overcoming PD-L1-dependent immune evasion.
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Affiliation(s)
- Chushu Li
- Zhongshan-Xuhui Hospital, Institutes of Biomedical Sciences (visiting), Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Fudan University, Shanghai, China
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Chi
- Zhongshan-Xuhui Hospital, Shanghai Xuhui Central Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Fudan University, Shanghai, China
| | - Shouyan Deng
- Zhongshan-Xuhui Hospital, Institutes of Biomedical Sciences (visiting), Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Fudan University, Shanghai, China
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huanbin Wang
- Zhongshan-Xuhui Hospital, Institutes of Biomedical Sciences (visiting), Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Fudan University, Shanghai, China
| | - Han Yao
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yungang Wang
- Zhongshan-Xuhui Hospital, Shanghai Xuhui Central Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Fudan University, Shanghai, China
| | - Dawei Chen
- Innomodels Biotechnology (Beijing) Co., Ltd, Beijing, China
| | - Xun Guo
- Innomodels Biotechnology (Beijing) Co., Ltd, Beijing, China
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fang He
- Zhongshan-Xuhui Hospital, Shanghai Xuhui Central Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Fudan University, Shanghai, China
| | - Jie Xu
- Zhongshan-Xuhui Hospital, Shanghai Xuhui Central Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Fudan University, Shanghai, China
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Gálvez NMS, Bohmwald K, Pacheco GA, Andrade CA, Carreño LJ, Kalergis AM. Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases. Clin Microbiol Rev 2021; 34:e00232-20. [PMID: 33361143 PMCID: PMC7950362 DOI: 10.1128/cmr.00232-20] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.
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Affiliation(s)
- Nicolás M S Gálvez
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Karen Bohmwald
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gaspar A Pacheco
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina A Andrade
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leandro J Carreño
- Millennium Institute on Immunology and Immunotherapy, Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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Natural Killer T Cells in Various Mouse Models of Hepatitis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1782765. [PMID: 33506011 PMCID: PMC7810568 DOI: 10.1155/2021/1782765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 11/26/2020] [Accepted: 12/28/2020] [Indexed: 12/19/2022]
Abstract
Natural killer T (NKT) cells are a key component of innate immunity. Importantly, a growing body of evidence indicates that NKT cells play an integral role in various acute and chronic liver injuries. NKT cells participate in the progression of an injury through the secretion of cytokines, which promote neutrophil infiltration and enhance Fas ligand (FasL) and granzyme-mediated NKT cytotoxic activity. Therefore, examining the role of NKT cells in hepatic disease is critical for a comprehensive understanding of disease pathogenesis and may provide insight into novel approaches for treatment. For more than a century, mouse models that imitate the physiopathological conditions of human disease have served as a critical tool in biological and medical basic research, including studies of liver disease. Here, we review the role of NKT cells in various mouse models of hepatitis.
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11
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Sun S, Yang Q, Sheng Y, Fu Y, Sun C, Deng C. Investigational drugs with dual activity against HBV and HIV (Review). Exp Ther Med 2020; 21:35. [PMID: 33262821 PMCID: PMC7690342 DOI: 10.3892/etm.2020.9467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/14/2020] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis B (CHB) and acquired immunodeficiency syndrome (AIDS) are global public health problems that pose a significant health burden. Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection is common, as these viruses have similar transmission routes, such as blood transmission, sexual transmission and mother-to-child transmission. Coinfection frequently leads to accelerated disease progression. For individuals coinfected with HIV/HBV, combination antiretroviral therapy containing dual anti-HBV drugs is recommended. Certain studies have also indicated the benefits of antiretroviral drugs with anti-HBV activity in patients with coinfection. A total of four Food and Drug Administration-approved HIV drugs also have anti-HBV activity; namely, emtricitabine, lamivudine, tenofovir disoproxil fumarate and tenofovir alafenamide, which are all nucleoside reverse transcriptase inhibitors. However, various issues, including drug resistance and side effects, limit their application. Therefore, it is necessary to develop more drugs with dual activity against HBV and HIV. The present review outlines the mechanisms, safety and efficacy of certain drugs that have been investigated for this purpose.
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Affiliation(s)
- Shiyu Sun
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Infection and Immunity Laboratory, Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Qing Yang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Infection and Immunity Laboratory, Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Yunjian Sheng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Infection and Immunity Laboratory, Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Yi Fu
- School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Changfeng Sun
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Infection and Immunity Laboratory, Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Cunliang Deng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.,Department of Infection and Immunity Laboratory, Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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12
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PD-L1 regulates tumorigenesis and autophagy of ovarian cancer by activating mTORC signaling. Biosci Rep 2020; 39:221398. [PMID: 31799599 PMCID: PMC6923342 DOI: 10.1042/bsr20191041] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 11/13/2019] [Accepted: 11/25/2019] [Indexed: 01/09/2023] Open
Abstract
PD-L1 is a well-known immune co-stimulatory molecule that regulates tumour cell escape from immunity by suppressing the immune response. However, the clinical significance of PD-L1 in the progression of ovarian cancer is unclear. Our study demonstrated that PD-L1 is up-regulated in ovarian tumour tissue compared with its expression level in adjacent normal tissue. Furthermore, we confirmed that PD-L1 increases the proliferation of cancer cells by activating the AKT-mTORC signalling pathway, which is also enhanced by the expression of S6K, the substrate of mTORC. In addition, PD-L1 promotes the autophagy of ovarian cancer cells by up-regulating the expression of BECN1, a crucial molecule involved in the regulation of autophagy. In conclusion, PD-L1 may provide a target for the development of a novel strategy for the treatment of ovarian cancer.
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13
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Kölle J, Haag P, Vuorinen T, Alexander K, Rauh M, Zimmermann T, Papadopoulos NG, Finotto S. Respiratory infections regulated blood cells IFN-β-PD-L1 pathway in pediatric asthma. IMMUNITY INFLAMMATION AND DISEASE 2020; 8:310-319. [PMID: 32394602 PMCID: PMC7416032 DOI: 10.1002/iid3.307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 04/30/2020] [Indexed: 01/20/2023]
Abstract
Background Respiratory infections, in general, and rhinovirus infection specifically are the main reason for asthma exacerbation in children and programmed cell death protein 1 ligand (PD‐L1) expression inhibits T cell responses. Objective Could the interferon (IFN) type I expression in peripheral blood mononuclear cells (PBMCs) improve disease exacerbation in pediatric asthma? Results Here we found increased level of PD‐L1 messenger RNA (mRNA) in total blood cells isolated from preschool children with virus‐induced asthma, with lower percentage of forced expiratory volume in 1 second and with high serum levels of the C‐reactive‐protein. Conclusions and Clinical Relevance These data indicate that, in the presence of infection in the airways of preschool children, worse asthma is associated with induced PD‐L1 mRNA expression in blood cells. Further, type I IFN, IFN‐β, a cytokine that is involved in the clearance of infections, was found to be associated with a better lung function in asthmatic children. These data suggest that improving peripheral blood IFN type I expression in PBMCs in pediatric asthma could improve disease exacerbation due to suppressing PD‐L1 expression in blood cells.
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Affiliation(s)
- Julia Kölle
- Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Patricia Haag
- Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Tytti Vuorinen
- Department of Virology, University of Turku, Turku, Finland
| | - Kiefer Alexander
- Department of Allergy and Pneumology, Children's Hospital, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Manfred Rauh
- Department of Allergy and Pneumology, Children's Hospital, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Theodor Zimmermann
- Department of Allergy and Pneumology, Children's Hospital, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Nikolaos G Papadopoulos
- Allergy and Clinical Immunology Unit, 2nd Pediatric Clinic, National and Kapodistrian University of Athens, Athens, Greece.,Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK
| | - Susetta Finotto
- Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
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14
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McNerney KO, Karageorgos SA, Hogarty MD, Bassiri H. Enhancing Neuroblastoma Immunotherapies by Engaging iNKT and NK Cells. Front Immunol 2020; 11:873. [PMID: 32457760 PMCID: PMC7225357 DOI: 10.3389/fimmu.2020.00873] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 04/16/2020] [Indexed: 12/13/2022] Open
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and significant treatment-related morbidities associated with current standard of care therapies belie the critical need for more tolerable and effective treatments for this disease. While the monoclonal antibody dinutuximab has demonstrated the potential for immunotherapy to improve overall NB outcomes, the 5-year overall survival of high-risk patients has not yet substantially changed. The frequency and type of invariant natural killer T cells (iNKTs) and natural killer cells (NKs) has been associated with improved outcomes in several solid and liquid malignancies, including NB. Indeed, iNKTs and NKs inhibit tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs), kill cancer stem cells (CSCs) and neuroblasts, and robustly secrete cytokines to recruit additional immune effectors. These capabilities, and promising pre-clinical and early clinical data suggest that iNKT- and NK-based therapies may hold promise as both stand-alone and combination treatments for NB. In this review we will summarize the biologic features of iNKTs and NKs that confer advantages for NB immunotherapy, discuss the barriers imposed by the NB tumor microenvironment, and examine the current state of such therapies in pre-clinical models and clinical trials.
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Affiliation(s)
- Kevin O McNerney
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Spyridon A Karageorgos
- School of Medicine, European University Cyprus, Nicosia, Cyprus.,Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Michael D Hogarty
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Hamid Bassiri
- Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, United States
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15
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Escoin-Perez C, Blasco S, Juan-Vidal O. Immune checkpoint inhibitors in special populations. A focus on advanced lung cancer patients. Lung Cancer 2020; 144:1-9. [PMID: 32278215 DOI: 10.1016/j.lungcan.2020.03.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/25/2020] [Accepted: 03/29/2020] [Indexed: 12/13/2022]
Abstract
Immune checkpoint inhibitors (ICIs), including those targeting programmed cell death 1 (PD-1), its ligand 1 (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have become the standard treatment for several malignancies, including lung cancer. However, some patient populations have been routinely excluded from clinical trials or are underrepresented in these studies, as is the case of elderly patients or patients with poor performance status, brain metastases, solid organ transplant, autoimmune diseases, chronic viral infections (such as human immunodeficiency virus or chronic viral hepatitis B and C), or organ dysfunction. Thus, the safety and efficacy of ICIs in these special populations is still unclear, despite regulatory approval of these agents. This review analyzes and summarizes the available information on the efficacy and safety of ICIs in these special populations, focusing on patients with lung cancer.
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Affiliation(s)
- Corina Escoin-Perez
- Department of Medical Oncology, Hospital Universitario de La Ribera, Crta. Corbera, Km1. 46600 Alzira, Valencia, Spain.
| | - Sara Blasco
- Department of Medical Oncology, Hospital de Sagunto, Av. Ramón y Cajal, s/n. 46520 Sagunto, Valencia, Spain.
| | - Oscar Juan-Vidal
- Department of Medical Oncology, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106. 46026, Valencia, Spain.
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16
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Yakoub AM, Schülke S. A Model for Apoptotic-Cell-Mediated Adaptive Immune Evasion via CD80-CTLA-4 Signaling. Front Pharmacol 2019; 10:562. [PMID: 31214024 PMCID: PMC6554677 DOI: 10.3389/fphar.2019.00562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 05/06/2019] [Indexed: 12/22/2022] Open
Abstract
Apoptotic cells carry a plethora of self-antigens but they suppress eliciting of innate and adaptive immune responses to them. How apoptotic cells evade and subvert adaptive immune responses has been elusive. Here, we propose a novel model to understand how apoptotic cells regulate T cell activation in different contexts, leading mostly to tolerogenic responses, mainly via taking control of the CD80-CTLA-4 coinhibitory signal delivered to T cells. This model may facilitate understanding of the molecular mechanisms of autoimmune diseases associated with dysregulation of apoptosis or apoptotic cell clearance, and it highlights potential therapeutic targets or strategies for treatment of multiple immunological disorders.
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Affiliation(s)
- Abraam M Yakoub
- Department of Molecular and Cellular Physiology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Stefan Schülke
- Vice President's Research Group: Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany
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17
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Nivolumab induced inflammation of seborrheic keratoses: a novel cutaneous manifestation in a metastatic melanoma patient. Melanoma Res 2019; 28:475-477. [PMID: 29965880 DOI: 10.1097/cmr.0000000000000477] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Immune checkpoint inhibitors targeting the programmed cell death (PD)-1 receptor have dramatically changed the landscape of metastatic melanoma treatment. Nevertheless, these immuno-modulatory agents have associated side effects, including dermatologic manifestations. To this end, we report a patient with metastatic melanoma that was treated with a PD-1 inhibitor, and subsequently developed inflammation of existing seborrheic keratosis lesions and new verrucous keratoses, a cutaneous side effect that has not been previously reported to our knowledge. The etiology of seborrheic and verrucous keratoses is not well understood, although their physical and histopathologic similarities to chronic viral-derived lesions, such as human papilloma virus, suggest a potential viral association. Chronic viral infections are known to result in T-cell tolerance because of persistent antigen stimulation. PD-1 inhibition is able to reinvigorate exhausted T cells, which are accordingly able to decrease viral load. Thus, the inflammatory reaction, seen in our patient, may be the result of PD-1 inhibition reactivating virally driven T lymphocytes.
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18
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Wang H, Yao H, Li C, Shi H, Lan J, Li Z, Zhang Y, Liang L, Fang JY, Xu J. HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. Nat Chem Biol 2018; 15:42-50. [PMID: 30397328 DOI: 10.1038/s41589-018-0161-x] [Citation(s) in RCA: 215] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 09/20/2018] [Indexed: 02/05/2023]
Abstract
Expression of programmed cell death 1 (PD-1) ligand 1 (PD-L1) protects tumor cells from T cell-mediated immune surveillance, and immune checkpoint blockade (ICB) therapies targeting PD-1 and PD-L1 have exhibited significant clinical benefits. However, the relatively low response rate and observed ICB resistance highlight the need to understand the molecular regulation of PD-L1. Here we show that HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. HIP1R physically interacts with PD-L1 and delivers PD-L1 to the lysosome through a lysosomal targeting signal. Depletion of HIP1R in tumor cells caused PD-L1 accumulation and suppressed T cell-mediated cytotoxicity. A rationally designed peptide (PD-LYSO) incorporating the lysosome-sorting signal and the PD-L1-binding sequence of HIP1R successfully depleted PD-L1 expression in tumor cells. Our results identify the molecular machineries governing the lysosomal degradation of PD-L1 and exemplify the development of a chimeric peptide for targeted degradation of PD-L1 as a crucial anticancer target.
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Affiliation(s)
- Huanbin Wang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Han Yao
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Chushu Li
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Hubing Shi
- Division of Cancer Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Jiang Lan
- Division of Cancer Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Zhaoli Li
- State Key Lab of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yao Zhang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Lunxi Liang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China.,Gastroenterology Department, Changsha Central Hospital, Changsha, China
| | - Jing-Yuan Fang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jie Xu
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China.
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19
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Cui C, Yu B, Jiang Q, Li X, Shi K, Yang Z. The roles of PD-1/PD-L1 and its signalling pathway in gastrointestinal tract cancers. Clin Exp Pharmacol Physiol 2018; 46:3-10. [PMID: 30161295 DOI: 10.1111/1440-1681.13028] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 08/24/2018] [Accepted: 08/26/2018] [Indexed: 12/31/2022]
Abstract
Cancer immunotherapy has been increasingly applied in the treatment of advanced malignancies. Consequently, immune checkpoints have become a major concern. As PD-1 is an important immunomodulatory protein, the blockade of PD-1 and its ligand PD-L1 is a promising tumour immunotherapy for human carcinoma. In this review, we first discuss the role of the PD-1/PD-L1 interaction in gastrointestinal tract cancers. Targeting PD-1 and PD-L1 in immune cells and tumour cells may show remarkable efficiency in gastrointestinal tract cancers. Second, the PD-1/PD-L1-associated signalling pathway involved in cancer immunotherapy in gastrointestinal tract cancers is discussed. Most importantly, this review summarizes the PD-1/PD-L1-targeted immunotherapy combinations with relevant signalling pathways, which may result in a breakthrough for the treatment of gastrointestinal tract cancers, such as gastric cancer, colorectal cancer and liver cancer. Meanwhile, the review provides a deeper insight into the mechanism of checkpoint blockade immunotherapies.
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Affiliation(s)
- Chunguo Cui
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Bo Yu
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qi Jiang
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xingfang Li
- 2nd Hospital of Jilin University, Changchun City, China
| | - Kaiyao Shi
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zecheng Yang
- 2nd Hospital of Jilin University, Changchun City, China
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20
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Banna GL, Passiglia F, Colonese F, Canova S, Menis J, Addeo A, Russo A, Cortinovis DL. Immune-checkpoint inhibitors in non-small cell lung cancer: A tool to improve patients' selection. Crit Rev Oncol Hematol 2018; 129:27-39. [PMID: 30097235 DOI: 10.1016/j.critrevonc.2018.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 06/16/2018] [Accepted: 06/18/2018] [Indexed: 12/15/2022] Open
Abstract
The identification of reliable predictive biomarkers of efficacy or resistance to immune-oncology (I-O) agents is a major issue for translational research and clinical practice. However, along with PDL1 and molecular features other clinical, radiological and laboratory factors can be considered for the selection of those patients who would not be the best candidate for immune-checkpoint inhibitors (ICPIs). We examined these factors, emerging from the results of currently available studies in non-small cell lung cancer (NSCLC), aiming to provide a useful and manageable tool which can help Oncologists in their everyday clinical practice. A thorough patient evaluation and close clinical monitoring, due to limited, early or inconclusive currently available data, should be deserved for patients with a pre-existing symptomatic chronic obstructive pulmonary disease, age >75 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 1, a time to progression (TTP) < three months and progressive disease (PD) as the best response to the previous treatment, hepatitis or HIV-infections, high neutrophil to lymphocyte ratio (NLR), or on treatment with high-dose steroids, when the use of ICPIs is considered. Limited data are available to consider that ICPIs are safe in patients with interstitial lung disease, bronchiolitis obliterans organizing pneumonia and autommune diseases. Early evidence on steroids, vaccinations and antibiotics suggest their possible interaction with ICPIs and need to be more investigated in clinical trials. Oncogene-addicted NSCLC harboring EGFR-mutations and low tumor-infiltrating T-lymphocytes (TILs) seems not to gain benefit from I-O.
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Affiliation(s)
- Giuseppe Luigi Banna
- Division of Medical Oncology, Cannizzaro Hospital, Via Messina 829, 95126, Catania, Italy.
| | - Francesco Passiglia
- Department of Surgical, Oncological and Stomatological Disciplines, University of Palermo, Italy
| | | | | | - Jessica Menis
- Department of Oncology Medicine, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Alfredo Addeo
- Oncology Department, University Hospital Geneva, 1205 Geneva, Switzerland
| | - Antonio Russo
- Department of Surgical, Oncological and Stomatological Disciplines, University of Palermo, Italy
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21
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Xu Y, Wang Z, Du X, Liu Y, Song X, Wang T, Tan S, Liang X, Gao L, Ma C. Tim-3 blockade promotes iNKT cell function to inhibit HBV replication. J Cell Mol Med 2018; 22:3192-3201. [PMID: 29602251 PMCID: PMC5980221 DOI: 10.1111/jcmm.13600] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 02/06/2018] [Indexed: 12/23/2022] Open
Abstract
Increased expression of T cell immunoglobulin and mucin domain-3 (Tim-3) on invariant natural killer T (iNKT) cells is reported in chronic hepatitis B virus (HBV) infection. However, whether Tim-3 regulates iNKT cells in chronic HBV condition remains unclear. In this study, our results showed that the expression of Tim-3 was up-regulated on hepatic iNKT cells from HBV-transgenic (Tg) mice or iNKT cells stimulated with α-galactosylceramide (α-Galcer). Compared with Tim-3- iNKT cells, Tim-3+ iNKT cells expressed more IFN-γ, IL-4 and CD107a, indicating a strong relationship between Tim-3 and iNKT cell activation. Constantly, treatment of Tim-3 blocking antibodies significantly enhanced the production of IFN-γ, TNF-α, IL-4 and CD107a in iNKT cells both in vivo and in vitro. This Tim-3- mediated suppression of iNKT cells was further confirmed in Tim-3 knockout (KO) mice. Moreover, Tim-3 blockade promoted α-Galcer-triggered inhibition of HBV replication, displaying as the decreased HBV DNA and HBsAg level in serum, and down-regulated pgRNA expression in liver tissues. Collectively, our data, for the first time, demonstrated the potential role of Tim-3 blockade in promoting iNKT cell-mediated HBV inhibition. Therefore, combination of α-Galcer with Tim-3 blockade might be a promising approach in chronic hepatitis B therapy.
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Affiliation(s)
- Yong Xu
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Zehua Wang
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Xianhong Du
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Yuan Liu
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Tixiao Wang
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Siyu Tan
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of EducationKey Laboratory of Infection and Immunity of Shandong ProvinceDepartment of ImmunologySchool of Basic Medical SciencesShandong UniversityJinanChina
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22
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Shissler SC, Lee MS, Webb TJ. Mixed Signals: Co-Stimulation in Invariant Natural Killer T Cell-Mediated Cancer Immunotherapy. Front Immunol 2017; 8:1447. [PMID: 29163518 PMCID: PMC5671952 DOI: 10.3389/fimmu.2017.01447] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 10/17/2017] [Indexed: 12/31/2022] Open
Abstract
Invariant natural killer T (iNKT) cells are an integral component of the immune system and play an important role in antitumor immunity. Upon activation, iNKT cells can directly kill malignant cells as well as rapidly produce cytokines that stimulate other immune cells, making them a front line defense against tumorigenesis. Unfortunately, iNKT cell number and activity are reduced in multiple cancer types. This anergy is often associated with upregulation of co-inhibitory markers such as programmed death-1. Similar to conventional T cells, iNKT cells are influenced by the conditions of their activation. Conventional T cells receive signals through the following three types of receptors: (1) T cell receptor (TCR), (2) co-stimulation molecules, and (3) cytokine receptors. Unlike conventional T cells, which recognize peptide antigen presented by MHC class I or II, the TCRs of iNKT cells recognize lipid antigen in the context of the antigen presentation molecule CD1d (Signal 1). Co-stimulatory molecules can positively and negatively influence iNKT cell activation and function and skew the immune response (Signal 2). This study will review the background of iNKT cells and their co-stimulatory requirements for general function and in antitumor immunity. We will explore the impact of monoclonal antibody administration for both blocking inhibitory pathways and engaging stimulatory pathways on iNKT cell-mediated antitumor immunity. This review will highlight the incorporation of co-stimulatory molecules in antitumor dendritic cell vaccine strategies. The use of co-stimulatory intracellular signaling domains in chimeric antigen receptor-iNKT therapy will be assessed. Finally, we will explore the influence of innate-like receptors and modification of immunosuppressive cytokines (Signal 3) on cancer immunotherapy.
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Affiliation(s)
- Susannah C Shissler
- Department of Microbiology and Immunology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Michael S Lee
- Department of Microbiology and Immunology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Tonya J Webb
- Department of Microbiology and Immunology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States
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Forsythoside A Inhibits BVDV Replication via TRAF2-Dependent CD28-4-1BB Signaling in Bovine PBMCs. PLoS One 2016; 11:e0162791. [PMID: 27617959 PMCID: PMC5019491 DOI: 10.1371/journal.pone.0162791] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 08/28/2016] [Indexed: 01/02/2023] Open
Abstract
Bovine viral diarrhea virus (BVDV), the causative agent of bovine viral diarrhea/mucosal disease (BVD/MD), is an important pathogen of cattle and other wild animals throughout the world. BVDV infection typically leads to an impaired immune response in cattle. In the present study, we investigated the effect of Forsythoside A (FTA) on BVDV infection of bovine peripheral blood mononuclear cells (PBMCs). We found that Forsythoside A could not only promote proliferation of PBMCs and T cells activation but also inhibit the replication of BVDV as well as apoptosis induced by BVDV. FTA treatment could counteract the BVDV-induced overproduction of IFN-γ to maintain the immune homeostasis in bovine PBMCs. At same time, FTA can enhance the secretion of IL-2. What's more, BVDV promotes the expression of CD28, 4-1BB and TRAF-2, which can be modulated by FTA. Our data suggest that FTA protects PBMCs from BVDV infection possibly via TRAF2-dependent CD28-4-1BB signaling, which may activate PBMCs in response to BVDV infection. Therefore, this aids in the development of an effective adjuvant for vaccines against BVDV and other specific FTA-based therapies for preventing BVDV infection.
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Yuksel M, Xiao X, Tai N, Vijay M, Gülden E, Beland K, Lapierre P, Alvarez F, Hu Z, Colle I, Ma Y, Wen L. The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model. Clin Exp Immunol 2016; 186:164-176. [PMID: 27414259 DOI: 10.1111/cei.12843] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2016] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (Tregs ), which had decreased programmed death (PD)-1 expression. Splenic Tregs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+ T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8+ T effectors, facilitating the induction of AIH and persistent liver damage.
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Affiliation(s)
- M Yuksel
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium.,Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - X Xiao
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Department of Nephrology, Qilu Hospital, Shandong University, China
| | - N Tai
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - Manakkat Vijay
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - E Gülden
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - K Beland
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - P Lapierre
- Immunovirology Laboratory, Institut National De La Recherche Scientifique, INRS-Institut Armand-Frappier, Laval, Québec, Canada
| | - F Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - Z Hu
- Department of Nephrology, Qilu Hospital, Shandong University, China
| | - I Colle
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium
| | - Y Ma
- Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - L Wen
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.
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25
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Zou ZQ, Wang L, Wang K, Yu JG. Innate immune targets of hepatitis B virus infection. World J Hepatol 2016; 8:716-725. [PMID: 27330680 PMCID: PMC4911505 DOI: 10.4254/wjh.v8.i17.716] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 05/19/2016] [Accepted: 06/01/2016] [Indexed: 02/06/2023] Open
Abstract
Approximately 400 million people are chronically infected with hepatitis B virus (HBV) globally despite the widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection.
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Affiliation(s)
- Zhi-Qiang Zou
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Li Wang
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Kai Wang
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Ji-Guang Yu
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
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26
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Yang Q, Bhandoola A. The development of adult innate lymphoid cells. Curr Opin Immunol 2016; 39:114-20. [PMID: 26871595 DOI: 10.1016/j.coi.2016.01.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 01/13/2016] [Accepted: 01/14/2016] [Indexed: 01/21/2023]
Abstract
Innate lymphoid cells (ILC) are a specialized family of effector lymphocytes that transcriptionally and functionally mirror effector subsets of T cells, but differ from T cells in that they lack clonally distributed adaptive antigen receptors. Our understanding of this family of lymphocytes is still in its infancy. In this review, we summarize current understanding and discuss recent insights into the cellular and molecular events that occur during early ILC development in adult mice. We discuss how these events overlap and diverge with the early development of adaptive T cells, and how they may influence the molecular and functional properties of mature ILC.
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Affiliation(s)
- Qi Yang
- T-Cell Biology and Development Unit, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Avinash Bhandoola
- T-Cell Biology and Development Unit, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States.
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27
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Yang F, Jin H, Wang J, Sun Q, Yan C, Wei F, Ren X. Adoptive Cellular Therapy (ACT) for Cancer Treatment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 909:169-239. [PMID: 27240459 DOI: 10.1007/978-94-017-7555-7_4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Adoptive cellular therapy (ACT) with various lymphocytes or antigen-presenting cells is one stone in the pillar of cancer immunotherapy, which relies on the tumor-specific T cell. The transfusion of bulk T-cell population into patients is an effective treatment for regression of cancer. In this chapter, we summarize the development of various strategies in ACT for cancer immunotherapy and discuss some of the latest progress and obstacles in technical, safety, and even regulatory aspects to translate these technologies to the clinic. ACT is becoming a potentially powerful approach to cancer treatment. Further experiments and clinical trials are needed to optimize this strategy.
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Affiliation(s)
- Fan Yang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
| | - Hao Jin
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
| | - Jian Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
| | - Qian Sun
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
| | - Cihui Yan
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
| | - Feng Wei
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, Tianjin, China.
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28
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Kasi PM, Block MS, Ansell SM. Treatment of HIV/AIDS associated cancers with immunotherapy targeting PD-1/PD-L1 instead of chemotherapy. Med Hypotheses 2015; 86:129-31. [PMID: 26559886 DOI: 10.1016/j.mehy.2015.11.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 11/01/2015] [Indexed: 10/22/2022]
Abstract
The role of immunodeficiency in the pathogenesis of both AIDS-defining and non-AIDS defining cancers cannot be over-emphasized. Multiple studies and meta-analyses show that risk of these malignancies exponentially rises as the CD4 cell counts fall. Furthermore, treatment of these cancers in patients who have HIV/AIDS is complex and challenging due to the underlying immunosuppression and risk for infections. Often, the diagnosis of some of these malignancies is made at the same time as the diagnosis of HIV/AIDS, which further complicates treatment decisions, especially when CD4 counts are extremely low. The risks of giving chemotherapy in the setting of severe immunosuppression warrants a paradigm shift in how we should be treating malignancies in patients with HIV/AIDS. We hypothesize and propose that alongside combination antiretroviral therapy (cART), some patients with HIV/AIDS associated malignancies should be treated with immunotherapy targeting PD-1/PD-L1 pathway rather than chemotherapy. The rationale and basis for the new approach is presented.
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Affiliation(s)
- Pashtoon Murtaza Kasi
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Rochester, MN, United States.
| | - Matthew S Block
- Division of Oncology, College of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Stephen M Ansell
- Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN, United States
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29
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PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV. Case Rep Oncol Med 2015; 2015:737389. [PMID: 26448890 PMCID: PMC4581502 DOI: 10.1155/2015/737389] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Accepted: 08/30/2015] [Indexed: 12/21/2022] Open
Abstract
On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma). Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies) evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV), and/or human immunodeficiency virus (HIV) infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.
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30
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Integrative analysis of differentially expressed microRNAs of pulmonary alveolar macrophages from piglets during H1N1 swine influenza A virus infection. Sci Rep 2015; 5:8167. [PMID: 25639204 PMCID: PMC5389138 DOI: 10.1038/srep08167] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 01/08/2015] [Indexed: 12/15/2022] Open
Abstract
H1N1 swine influenza A virus (H1N1 SwIV) is one key subtype of influenza viruses with pandemic potential. MicroRNAs (miRNAs) are endogenous small RNA molecules that regulate gene expression. MiRNAs relevant with H1N1 SwIV have rarely been reported. To understand the biological functions of miRNAs during H1N1 SwIV infection, this study profiled differentially expressed (DE) miRNAs in pulmonary alveolar macrophages from piglets during the H1N1 SwIV infection using a deep sequencing approach, which was validated by quantitative real-time PCR. Compared to control group, 70 and 16 DE miRNAs were respectively identified on post-infection day (PID) 4 and PID 7. 56 DE miRNAs were identified between PID 4 and PID 7. Our results suggest that most host miRNAs are down-regulated to defend the H1N1 SwIV infection during the acute phase of swine influenza whereas their expression levels gradually return to normal during the recovery phase to avoid the occurrence of too severe porcine lung damage. In addition, targets of DE miRNAs were also obtained, for which bioinformatics analyses were performed. Our results would be useful for investigating the functions and regulatory mechanisms of miRNAs in human influenza because pig serves as an excellent animal model to study the pathogenesis of human influenza.
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31
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Li X, Wang Y, Chen Y. Cellular immune response in patients with chronic hepatitis B virus infection. Microb Pathog 2014; 74:59-62. [PMID: 25128091 DOI: 10.1016/j.micpath.2014.07.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 07/30/2014] [Accepted: 07/31/2014] [Indexed: 02/08/2023]
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32
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Payne KK, Bear HD, Manjili MH. Adoptive cellular therapy of cancer: exploring innate and adaptive cellular crosstalk to improve anti-tumor efficacy. Future Oncol 2014; 10:1779-94. [DOI: 10.2217/fon.14.97] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
ABSTRACT The mammalian immune system has evolved to produce multi-tiered responses consisting of both innate and adaptive immune cells collaborating to elicit a functional response to a pathogen or neoplasm. Immune cells possess a shared ancestry, suggestive of a degree of coevolution that has resulted in optimal functionality as an orchestrated and highly collaborative unit. Therefore, the development of therapeutic modalities that harness the immune system should consider the crosstalk between cells of the innate and adaptive immune systems in order to elicit the most effective response. In this review, the authors will discuss the success achieved using adoptive cellular therapy in the treatment of cancer, recent trends that focus on purified T cells, T cells with genetically modified T-cell receptors and T cells modified to express chimeric antigen receptors, as well as the use of unfractionated immune cell reprogramming to achieve optimal cellular crosstalk upon infusion for adoptive cellular therapy.
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Affiliation(s)
- Kyle K Payne
- Department of Microbiology & Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298, USA
| | - Harry D Bear
- Department of Microbiology & Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298, USA
- Department of Surgery, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298, USA
| | - Masoud H Manjili
- Department of Microbiology & Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298, USA
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Lawrenczyk A, Kim S, Wen X, Xiong R, Yuan W. Exploring the Therapeutic Potentials of iNKT Cells for Anti-HBV Treatment. Pathogens 2014; 3:563-76. [PMID: 25438012 PMCID: PMC4243429 DOI: 10.3390/pathogens3030563] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 06/23/2014] [Accepted: 06/23/2014] [Indexed: 12/14/2022] Open
Abstract
CD1d-restricted invariant NKT (iNKT) cells are a group of innate-like regulatory T cells that recognize lipid antigens. Both mouse modeling experiments and human clinical studies have suggested a key role for iNKT cells in anti-HBV immunity and these potent T cells can be explored as a novel therapeutic target for anti-HBV treatment. We aim to humanize mice in the CD1d/iNKT cell lipid presentation system and provide new research tools for identifying novel anti-HBV agents.
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Affiliation(s)
- Agnieszka Lawrenczyk
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Seil Kim
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Xiangshu Wen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Ran Xiong
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Weiming Yuan
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Cui L, Shi Y, Han Y, Fan D. Immunological basis of stem cell therapy in liver diseases. Expert Rev Clin Immunol 2014; 10:1185-96. [PMID: 24964800 DOI: 10.1586/1744666x.2014.930665] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Unbalanced immune cell populations or immune cell infiltration of the liver can disrupt the immune-privileged state of the liver, resulting in liver injury or fibrosis. Therefore, the treatment for liver diseases involves not only hepatic regeneration but also immunological regulation. Recent studies demonstrated that stem cells, especially mesenchymal stem cells, have the capacity for not only hepatic differentiation but also immunomodulation. In this respect, stem cell therapy could be a realistic aim for liver diseases by modulating the liver regenerative processes and down-regulating immune-mediated liver damage. In this review, we discuss in detail the importance of immune cells in liver injury and repair; the mechanism by which stem cells demonstrate an immune-tolerant phenotype that can be used for allogeneic transplantation; the effect of stem cell transplantation on immune-mediated diseases, especially liver diseases; and the mechanism by which stem cells improve the hepatic microenvironment.
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Affiliation(s)
- Lina Cui
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
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Changes of costimulatory molecule CD28 on circulating CD8+ T cells correlate with disease pathogenesis of chronic hepatitis B. BIOMED RESEARCH INTERNATIONAL 2014; 2014:423181. [PMID: 25013781 PMCID: PMC4071789 DOI: 10.1155/2014/423181] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 05/09/2014] [Accepted: 05/18/2014] [Indexed: 01/29/2023]
Abstract
Costimulatory signals are critical for antiviral immunity. The aim of this study was to evaluate the change of costimulatory molecule CD28 on circulating CD8+ T cells in chronic hepatitis B patients (CHB). Seventy CHB patients and fifty-six healthy controls were included, and forty-eight CHB patients were recruited for 52 weeks of longitudinal investigation. The proportions of circulating CD8+CD28+ and CD8+CD28− subpopulations were determined by flow cytometry, and the CD8+CD28+/CD8+CD28− T cells ratio was calculated. Compared with the subpopulation in healthy controls, high proportions of CD8+CD28− subpopulation were observed in CHB patients. Similarly, the CD8+CD28+/CD8+CD28− T cells ratio was significantly decreased in CHB patients compared with healthy controls and correlated significantly with hepatitis B virus (HBV) loads. High proportions of CD8+CD28− subpopulation and low CD8+CD28+/CD8+CD28− T cells ratio were observed in hepatitis B e antigen- (HBeAg-) positive individuals as compared with that in HBeAg-negative subjects. A significant decrease in CD8+CD28− subpopulation, increase in CD8+CD28+ subpopulation, and CD8+CD28+/CD8+CD28− T cells ratio were seen in those patients who received efficient antiviral therapy. Thus, aberrant CD28 expression on circulating CD8+ T cells and the CD8+CD28+/CD8+CD28− T cells ratio reflect the dysregulation of T cell activation and are related to the pathogenesis of chronic HBV infection.
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Singh AK, Gaur P, Das SN. Natural killer T cell anergy, co-stimulatory molecules and immunotherapeutic interventions. Hum Immunol 2013; 75:250-60. [PMID: 24373798 DOI: 10.1016/j.humimm.2013.12.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 10/28/2013] [Accepted: 12/15/2013] [Indexed: 01/05/2023]
Abstract
Natural killer T (NKT) cells are a unique subset of glycolipid-reactive T lymphocytes that share properties with natural killer (NK) cells. These lymphocytes can produce array of cytokines and chemokines that modulate the immune response, and play a pivotal role in cancer, autoimmunity, infection and inflammation. Owing to these properties, NKT cells have gained attentions for its potential use in antitumor immunotherapies. To date several NKT cell-based clinical trials have been performed in patients with cancer using its potent ligand α-galactosylceramide (α-GalCer). However, inconsistent therapeutic benefit, and inevitable health risks associated with drug dose and NKT cell activation have been observed. α-GalCer-activated NKT cells become anergic and produce both Th1 and Th2 cytokines that may function antagonistically, limiting the desired effector functions. Besides, various co-stimulatory and signaling molecules such as programmed death-1 (PD-1; CD279), casitas B-cell lymphoma-b (Cbl-b) and CARMA1 have been shown to be implicated in the induction of NKT cell anergy. In this review, we discuss the role of such key regulators and their functional mechanisms that may facilitate the development of improved approaches to overcome NKT cell anergy. In addition, we describe the evidences indicating that tailored-ligands can optimally activate NKT cells to obtain desired immune responses.
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Affiliation(s)
- Avadhesh Kumar Singh
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India.
| | - Poonam Gaur
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India.
| | - Satya N Das
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India.
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Mattner J. Natural killer T (NKT) cells in autoimmune hepatitis. Curr Opin Immunol 2013; 25:697-703. [PMID: 24148235 PMCID: PMC4013545 DOI: 10.1016/j.coi.2013.09.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 09/15/2013] [Accepted: 09/27/2013] [Indexed: 02/08/2023]
Abstract
Natural killer T (NKT) cells represent an innate-like lymphocyte population endowed with unique antigen recognition and tissue distribution features. Their abundance in the microvascular compartments of the liver allows NKT cells to immediately respond to lipid antigens and soluble factors circulating through the portal vein system by releasing tremendous amounts of different cytokines and chemokines. Subsequently, dependent on the nature of the lipid antigen encountered as well as the accessory signal(s) provided, NKT cells not only contribute to the maintenance of immune tolerance, but also direct adverse immune reactions locally and systemically. Focusing on their potent immunomodulatory features and their interactions with various innate and adaptive immune cells, the role of NKT cells in perpetuating the loss of liver-specific immune tolerance will be discussed.
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Affiliation(s)
- Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
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